Abstract Misuse of prescription opioids and heroin is a global epidemic, with an estimated 33 million people misusing opioids worldwide and 2.6 million individuals in the U.S. meeting criteria for an opioid use disorder. This public health crisis is occurring on the background of a precipitous increase in the availability of marijuana, both in the U.S. and worldwide. Marijuana use is at peak levels in the U.S. ? in 2014, 22.2 million individuals 12 years and older reported past month marijuana use and 8.4 million individuals reported daily/near-daily marijuana use. Marijuana and opioids are the two most commonly misused illicit drug classes (with many more taking these drugs therapeutically); however, despite these high rates of use, there are no carefully controlled human data available on their co-use, specifically in regard to drug response, abuse-related measures and safety outcomes. Thus, the current project aims to explore the 1) safety/physiological effects of marijuana and opioid combinations, 2) impact of marijuana use on opioid response and opioid drug-taking, 3) effects of opioid use on marijuana drug-taking, and 4) behavioral and cognitive effects of combined opioid- cannabinoid use. Two independent inpatient studies will be conducted during this 4-year project and each will utilize a randomized, within-subject, double-blind, double-dummy, placebo-controlled design and will enroll samples of non-physically dependent recreational opioid users with histories of marijuana use. Study 1 will examine the effects of smoked marijuana pre-treatment, over a range of THC concentrations (0, 5 &15% THC), on intranasal oxycodone (0, 15 & 30 mg) response, using a full battery of pharmacodynamic outcomes, including safety/physiological response and abuse-related subjective and observer-rated effects. Secondary aims will examine the psychomotor/cognitive effects across the dose conditions. Study 2 will explore 1) the effects of smoked marijuana pre-treatment (0, 15% THC) on intranasal oxycodone (0, 15 & 30 mg) self- administration, and 2) intranasal oxycodone pre-treatment (0, 30 mg) on smoked marijuana (0, 5 & 15% THC) self-administration. Overall, these studies will provide some of the first empirical data on the interaction effects of the two most commonly misused drug classes, providing information on the safety impact, physiological effects and abuse-related effects of their co-use. These findings will be highly relevant to public health considerations, will help determine the risk profile of marijuana and opioid interactions, and will provide new controlled information relevant to clinical practice, prescribing, and public safety.